G Dell'Omo

Microalbuminuria and endothelial dysfunction in essential hypertension

Microalbuminuria (urinary albumin excretion between 20 and 200 micrograms/min) and endothelial dysfunction coexist in patients with essential hypertension. To evaluate whether the two phenomena are related and the determinants of that association, we recruited 10 untreated males with essential hypertension and microalbuminuria without diabetes to be compared with an equal number of matched patients with essential hypertension excreting albumin in normal amounts and 10 normal controls. The status of endothelial function was inferred from circulating von Willebrand Factor antigen (vWF), a glycoprotein secreted in greater amounts when the vascular endothelium is damaged. vWF concentrations were higher in hypertensive patients with microalbuminuria than in hypertensive patients without and controls. Individual vWF and urine albumin-excretion values were correlated (r = 0.55, p < 0.002). Blood pressure correlated with both urinary albumin excretion and vWF. Left ventricular mass index and minimal forearm vascular resistances were comparable in patients with hypertension and higher than in controls; total and low-density lipoprotein cholesterol, triglycerides, lipoprotein-a, Factor VII, and plasminogen activator inhibitor-1 did not differ. Fibrinogen was higher and creatinine clearance lower in microalbuminurics. Albuminuria in essential hypertension may reflect systemic dysfunction of the vascular endothelium, a structure intimately involved in permeability, haemostasis, fibrinolysis, and blood pressure control. This abnormality may have important physiopathological implications and expose these patients to increased cardiovascular risk.

Microalbuminuria, an integrated marker of cardiovascular risk in essential hypertension

This paper reviews the existing epidemiological and clinical evidence about the relationships of non-diabetic microalbuminuria with cardiovascular risk factors such as elevated blood pressure (BP), systolic particularly, cardiac hypertrophy, adverse metabolic status, smoking habits, elevated angiotensin II levels, endothelial dysfunction, acute and perhaps subclinical inflammation. Because of that unique property of reflecting the influence of so many clinically relevant parameters, microalbuminuria may legitimately be defined as an integrated marker of cardiovascular risk, an unique profile among the several prognostic predictors available to stratify risk in hypertensive patients. Recent cohort studies also showed associations with cardiovascular morbidity and mortality independently from conventional atherogenic factors. This behaviour, whose understanding still needs further elucidation, suggests to measure albuminuria and to screen patients at a higher absolute risk in whom preventive treatment is expected to be more beneficial than in those with a lower absolute risk.

Microalbuminuria and Pulse Pressure in Hypertensive and Atherosclerotic Men

To identify the biological covariates of microalbuminuria (albuminuria >/=15 microg/min) in nondiabetic subjects, brachial blood pressure, echocardiographic left ventricular mass, and other cardiovascular and metabolic parameters were evaluated in 211 untreated males (38 normal controls, 109 uncomplicated stage 1 to 3 essential hypertensives, and 64 patients with clinically stable atherosclerotic peripheral vascular disease either with [n=44] or without [n=20] essential hypertension) with normal cardiac and renal function. Compared with normoalbuminuric subjects, microalbuminuric subjects (n=67) were characterized by higher systolic blood pressure, comparable diastolic blood pressure, and, therefore, wider pulse pressure. Greater prevalence of hypertension, peripheral vascular disease, left ventricular hypertrophy, and reduced HDL cholesterol values further distinguished microalbuminuric from normoalbuminuric subjects in univariate comparisons. The risk of microalbuminuria increased by ascending pulse pressure quintiles in age-corrected logistic regression models, in which pulse pressure was more predictive than systolic pressure and was independent of mean pressure. When microalbuminuric status was regressed against a series of dichotomous (vascular and active smoker status) and continuous (age, pulse and mean pressure, left ventricular mass index, and HDL and LDL cholesterol) variables, only pulse pressure, left ventricular mass index, and smoking status were independent predictors. The association of increased albuminuria with wider pulse pressure, a correlate of the pulsatile hemodynamic load and conduit vessel stiffness as well as an important cardiovascular risk factor, may explain why microalbuminuria predicts cardiovascular events in nondiabetic subjects. The independence from concomitant vascular disease also suggests that wider pulse pressure, rather than representing a simple marker for atherosclerotic disease, influences albuminuria directly.

Early Left Ventricular Mechanics Abnormalities in Prehypertension: A Two-Dimensional Strain Echocardiography Study

BACKGROUND Prehypertension predicts established hypertension. In this study, the aim was to analyze left ventricular (LV) mechanics in borderline prehypertensive (pre-HT) and hypertensive (HT) subjects through two-dimensional (2D)-strain echocardiography and then evaluate possible relations between cardiac parameters and insulin metabolism (homeostasis model assessment of insulin resistance (HOMA(IR)). METHODS Seventy-four consecutive newly diagnosed, untreated HT were divided, on the basis of their office blood pressure (BP) measurements, confirmed by ambulatory BP monitoring (ABPM), in 41 borderline pre-HT (ABPM: 122.5 +/- 6.7/76.2 +/- 5.2 mm Hg) and 33 never-treated mild HT (ABPM: 138.3 +/- 7.3/87.6 +/- 7.1 mm Hg). Thirty-three healthy normotensive (NT) controls (ABPM: 114.8 +/- 6.3/73.1 +/- 6.1 mm Hg) (P < 0.0001) were also studied (NT). All subjects performed 2D color Doppler and pulsed-wave tissue Doppler imaging (PW-TDI). RESULTS Left ventricular mass (LVM) was significantly higher in pre-HT (39.2 +/- 8.7 g/m(2.7)) and in HT (43.6 +/- 8.5 g/m(2.7)) compared with NT (30.9 +/- 7.4 g/m(2.7)) (P < 0.0001). A mild LV diastolic dysfunction was found both with Doppler mitral flow velocity and PW-TDI at mitral annulus level analysis. Longitudinal 2D strain in pre-HT (-18.9% +/- 3.4) and in HT (-18.0% +/- 3.3) was significantly lower than in NT (-23.9% +/- 3.0) (P < 0.002). These LV abnormalities were associated with systolic ABPM, LVM, and HOMA(IR). CONCLUSIONS Early abnormalities of LV longitudinal systolic deformation were found both in pre-HT and HT, together with a mild LV diastolic dysfunction. In both groups this early cardiac systolic and diastolic dysfunction is associated to insulin resistance, systolic pressure load, and cardiac remodeling.

Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension

Treatment with calcium channel blocker (CCB)s, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment.

Amlodipine, Enalapril, and Dependent Leg Edema in Essential Hypertension

Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (n=10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (n=8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation limited additional fluid transfer. Both parameters normalized after drug withdrawal. Enalapril per se did not affect cutaneous vasomotion or leg weight but reduced the amount of dependent fluid extravasation by the CCB despite a persistent antagonism for postural vasoconstrictor responses.

Abnormal right ventricular mechanics in early systemic hypertension: a two-dimensional strain imaging study

AIMS To analyse the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function as assessed by two-dimensional strain imaging. METHODS AND RESULTS Longitudinal peak strain and strain rate (SR) were sampled by speckle-tracking methodology at the RV free wall and interventricular septum (IVS) and RV and left ventricular (LV) structure and function were evaluated by conventional echo-Doppler sonography in 89 never-treated, non-obese subjects with office BP values varying from the optimal to mildly hypertensive range. Data were analysed by 24 h systolic BP (SBP) tertiles (cut-offs: 117 and 130 mmHg, n = 29, 30, and 30, respectively), thus partitioning subjects with optimal BP from those with high-normal and mildly increased values. RV peak systolic strain and early diastolic SR decreased in the mid-BP third without further changes in the upper tertile. IVS thickened gradedly by increasing systemic 24 h SBP; posterior wall remodelled to a lesser extent and poorly related to BP load and LV mass index did not change. RV and IVS systolic and diastolic strain indices associated inversely with increasing septal thickness. Conventional right and left indices of global ventricular function, left atrial size, and estimated systolic pulmonary pressure did not differ. CONCLUSION Two-dimensional strain-assessed RV function is sensitive to increased systemic BP, even at levels below the conventional diagnostic limits for arterial hypertension. Subclinical RV systolic and diastolic abnormalities paralleled BP-driven septal remodelling, perhaps as a reflection of the crucial role played by IVS in RV function.

Simvastatin, capillary permeability, and acetylcholine-mediated vasomotion in atherosclerotic, hypercholesterolemic men

The aim of this study was to test the effect of high‐dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial‐mediated vasodilator responses in patients with hypercholesterolemic atherosclerosis.

Altered surface myoelectric signals in peripheral vascular disease: Correlations with muscle fiber composition

Conduction velocity (CV) and median frequency (MDF) during tetanic electrical stimulation of the tibialis anterior muscle were evaluated in patients with uncomplicated peripheral arterial occlusive disease. Results were analyzed with respect to biopsy determination of diameter and proportion of types 1 and 2 muscles fibers. Initial MDF and CV correlated positively with type 2, but not type 1 fiber diameter. Initial MDF was reduced bilaterally in patients with unilateral peripheral arterial occlusive disease as compared to normal subjects, indicating that chronic ischemia alone cannot explain the altered myoelectric signal. Physical training increased pain‐free walking distance and raised initial MDF, though CV remained unchanged. Fatigue indices were highly interrelated, but showed no correlation with any of the other evaluation variables. Thus, initial MDF, a correlate of type 2 muscle fiber distribution in chronically ischemic tibialis anterior muscles, is altered in peripheral vascular disease. However, muscle ischemia alone cannot explain all aspects of this abnormality.

Transvascular and Urinary Leakage of Albumin in Atherosclerotic and Hypertensive Men

Increased urine albumin is associated with atherosclerotic disease and predicts cardiovascular morbidity and mortality in nondiabetic populations. This finding is frequently postulated to reflect the impact of atherosclerotic damage on glomerular and systemic capillary permeability, an interesting but as yet untested hypothesis. The transcapillary escape rate of albumin (TERalb, the 1-hour decline rate of intravenous 125I-albumin, a measure of capillary macromolecular permeability), albuminuria, lipid levels, echocardiographic wall thickness, and insulin responses to oral glucose were measured in 30 untreated dipstick-negative lean men and clinically stable atherosclerotic peripheral vascular disease; tolerance to oral glucose was a requirement for inclusion in the study. Because hypertension per se might influence TERalb, the sample included either normotensive (n=18, 118+/-6/72+/-7 mm Hg) or hypertensive (n=12, 141+/-7/84+/-6 mmHg by 24-hour blood pressure monitoring) arteriopathic patients; 11 normal age- and gender-matched subjects (121+/-7/76+/-5 mmHg) were used as control subjects. TERalb was higher in patients (10.7+/-3.2 versus 7.4+/-1.7%/h, P<0.013), a difference that persisted after postload glucose, insulin, and lipid levels were accounted for by covariance analysis; atherosclerosis and hypertension together did not further impair vascular permeation to albumin. In contrast with TERalb, albuminuria was elevated only in the hypertensive subgroup; the 2 variables showed no relationship, even when the data were analyzed separately in normotensive and hypertensive subgroups. Urine albumin correlated positively with 24-hour blood pressure and wall thickness. Thus, systemic capillary permeability is altered in nondiabetic atherosclerotic patients independently from blood pressure levels, but this abnormality is not reflected by proportionate changes in albuminuria.